Continuing Education Activity

Lenvatinib is FDA-approved for the treatment of radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable or advanced hepatocellular carcinoma (HCC), advanced renal cell carcinoma (RCC), and advanced endometrial carcinoma. The multiple receptor tyrosine kinase inhibitor demonstrates potent antiangiogenic properties. The inhibition of the VEGF receptors prevents tumor angiogenesis, and the inhibition of FGFR, RET, PDGFRa, and KIT prevents further proliferation of malignant cells. The prescribing team should include primary care clinicians, oncologists, nurses, and pharmacists, crucial for early diagnosis, monitoring potential adverse effects, and optimizing dosage adjustments based on renal function, liver enzymes, body weight, and cardiac health. Routine monitoring for adverse effects like hypertension, cardiac impairment, QT interval prolongation, thyroid function changes, and reproductive considerations is necessary, along with patient education for better treatment outcomes and increased quality of life.

This activity highlights the mechanism of action, adverse event profile, and other key factors pertinent to interprofessional team members in managing patients with gastrointestinal or uterine cancers. Participating clinicians are informed to make decisions and optimize dosage regimens while minimizing adverse reactions.

Objectives:

• Identify the mechanism of action of lenvatinib in comparison to other tyrosine kinase inhibitors.
• Assess the adverse drug reactions of lenvatinib depending on past medical history and stage of malignancy.
• Evaluate the appropriate monitoring strategies for patients undergoing therapy with lenvatinib.
• Implement collaboration among interprofessional team members to improve treatment efficacy for patients with late-stage cancers who are prescribed lenvatinib.

Indications

Lenvatinib is a multiple receptor tyrosine kinase inhibitor demonstrating potent antiangiogenic properties indicated as monotherapy or combination therapy for certain malignancies. Lenvatinib is FDA-approved for radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable or advanced hepatocellular carcinoma (HCC), and advanced renal cell carcinoma (RCC).

Lenvatinib was approved for use in radioactive iodine-refractory DTC following a randomized, multicenter, placebo-controlled phase III study (REFLECT). The trial included 392 participants with radioactive iodine-refractory DTC and was subject to random assignment to either a treatment group of 24 mg lenvatinib daily or the placebo group at a 2:1 ratio. The treatment group demonstrated a median progression-free survival of 18.3 months and a response rate of 64.8% compared to the placebo group, 3.6 months and 1.5%, respectively. Both groups' overall survival did not show a notable difference, which may have been from the crossover between the placebo and treatment groups.[1] Lenvatinib has also been studied for use in anaplastic thyroid cancer but is currently not FDA-approved for this indication.[2]

The randomized, non-inferiority, phase III trial REFLECT demonstrated lenvatinib use in HCC as non-inferior to sorafenib, a kinase inhibitor approved to treat HCC. The trial also demonstrated lenvatinib prolonged progression-free survival rate by 7.3 months and an objective response rate of 24% compared to sorafenib, 3.6 months and 9%, respectively. The REFLECT phase III trial's efficacious results led to FDA approval for use as first-line therapy in unresectable or advanced HCC in patients not undergoing prior treatment. As per the American Association for the Study of Liver Diseases, patients diagnosed with HCC and Child-Turcotte-Pugh A cirrhosis, for whom atezolizumab plus bevacizumab and durvalumab plus tremelimumab are inappropriate, should be offered sorafenib or lenvatinib as the primary treatment choices. A systematic review and meta-analysis examined the safety and efficacy of lenvatinib versus sorafenib for treating HCC within real-world scenarios. The study encompassed 9 single-arm investigations and 6 comparative studies. The results indicated that lenvatinib yielded notably extended overall and progression-free survival, with a higher objective response rate and disease control rate than sorafenib. However, lenvatinib exhibited a higher prevalence of hypertension than sorafenib, with no significant distinction in hand-foot syndrome. These findings suggest that lenvatinib may confer superior efficacy outcomes in treatment for HCC, although the safety profiles between the 2 drugs are comparable.[3][4]

Lenvatinib was also approved as a combination therapy with everolimus for RCC based on a randomized phase II trial. The trial compared lenvatinib 24 mg as monotherapy to everolimus 5 mg monotherapy and lenvatinib 24 mg and everolimus 5 mg as combination therapy. The combination group demonstrated a lengthened progression-free survival of 14.6 months compared to the 5.5 months of everolimus monotherapy and 7.4 months of lenvatinib monotherapy. The combination therapy also showed prolonged overall survival compared to the monotherapies.[5] Lenvatinib, in conjunction with pembrolizumab, has gained FDA approval for treating patients with advanced endometrial carcinoma proficient in mismatch repair, as diagnosed by an FDA-sanctioned test or lacking high microsatellite instability.[6][7][8]

FDA Approved Indications

• Radioactive iodine-refractory DTC
• Unresectable or advanced HCC 
• Advanced RCC
• Endometrial cancer (in combination with pembrolizumab)

Off-Label Uses

• Anaplastic thyroid carcinoma [9][10]

Mechanism of Action

Lenvatinib exerts the mechanism of action via inhibition of multiple receptors of tyrosine kinases: VEGFR-1 (FLT1), VEGFR-2 (KDR), VEGFR-3 (FLT4), FGFR-1, FGFR-2, FGFR-3, FGFR-4, PDGFRa, RET, and c-KIT. Tumor growth depends on developing and proliferating new blood vessels (neovascularization). Tumor growth and angiogenesis occur when the ligands bind to their respective tyrosine kinase receptors in the cellular membrane, initiating an intracellular signal transduction phosphorylation cascade promoting angiogenesis and cell proliferation.

The inhibition of the VEGF receptors prevents tumor angiogenesis, and the inhibition of FGFR, RET, PDGFRα, and KIT prevents the further proliferation of malignant cells.[5] The concurrent inhibition of both receptor pathways results in the inhibition of nuclear signal transduction and simultaneous suppression of the activity of factors involved in tumor growth.

Pharmacokinetics

Absorption: For lenvatinib, peak plasma concentration (Tmax) is attained in 1 to 4 hours. When taken with a high-fat meal, the extent of absorption remains unaffected. However, the absorption rate decreases, delaying the median Tmax from 2 to 4 hours.

Distribution: The predicted mean steady-state volume of distribution for lenvatinib is 97 L (coefficient of variation [CV] of 30.2%). Lenvatinib demonstrates high protein binding, ranging from 97% to 99%, and this binding is not influenced by hepatic or renal function.

Metabolism: The primary metabolic pathways for lenvatinib involve enzymatic processes mediated by CYP3A, aldehyde oxidase, and non-enzymatic processes.

Excretion: The terminal elimination half-life of lenvatinib is approximately 28 hours. The primary pathway for lenvatinib excretion is through feces (64%), with a smaller fraction being eliminated via urine (25%).[11][12][13][14]

Administration

Available Dosage Forms and Strengths 

Lenvaitnib is available in 4 and 10-mg oral capsule dosages.[11] Lenvatinib can also be administered through a feeding tube as a suspension. The suspension is prepared with either water or apple juice. Following preparation, the suspension is administered orally at a consistent daily schedule, regardless of concurrent food intake. Similarly, the suspension is formulated with water specifically for feeding tube administration. The suspension is then introduced through the feeding tube daily. These instructions emphasize the importance of consistent timing to ensure optimal delivery of lenvatinib.

Adult Dosage

Radioactive iodine-refractory DTC: 24 mg orally daily

Advanced RCC

• First-line treatment: 20 mg orally daily with pembrolizumab for up to 2 years, then given as monotherapy. 
• Previously treated disease: 18 mg orally daily in combination with everolimus.

Unresectable HCC  

The suggested dose should be determined based on the patient's body weight: 

• 12 mg orally daily for patients' weight exceeding or equal to 60 kg.
• 8 mg orally daily for patients weighing less than 60 kg.

Advanced endometrial carcinoma: 20 mg orally daily with pembrolizumab for patients with non-microsatellite instability-high or non-mismatch repair deficient (dMMR) progressive disease who are not candidates for X-ray therapy or curative surgery.

Specific Patient Populations

Hepatic impairment: As noted earlier, lenvaitnib is metabolized enzymatically in the liver by CYP450 isoform CYP3A and aldehyde oxidase. For patients with severe hepatic impairment (Child-Pugh C), dose adjustment is required. For DTC, the prescribed dosage is 14 mg orally daily. For RCC, the recommended dosage is 10 mg orally daily. Similarly, for endometrial carcinoma, the suggested dosage is 10 mg orally daily.

Renal impairment: Dose modification is required for patients with severe renal impairment (creatinine clearance less than 30 mL/min). For DTC, the prescribed dosage is 14 mg orally daily. For RCC, the recommended dosage is 10 mg orally daily. Similarly, for endometrial carcinoma, the suggested dosage is 10 mg orally daily.

Pregnancy considerations: Lenvatinib can induce fetal harm in pregnant women based on animal studies. Research suggests embryotoxicity, fetotoxicity, and teratogenicity. In rats, doses ≥0.3 mg/kg led to reduced fetal body weight, delayed ossifications, and anomalies (parietal edema and tail abnormalities). In rabbits, doses ≥0.03 mg/kg caused anomalies (short tail, retro-esophageal subclavian artery) and increased post-implantation loss. Prescribing clinicians should advise pregnant women about the potential risk to the fetus.

Breastfeeding considerations: Limited clinical data exist regarding the clinical use of lenvatinib during breastfeeding. Due to the high plasma protein binding of more than 98%, the quantity excreted into milk is expected to be minimal. Nevertheless, the prolonged half-life of approximately 28 hours raises concerns about potential accumulation in the infant. Therefore, the manufacturer advises discontinuing breastfeeding during lenvatinib treatment and at least 1 week after the final dose.

Pediatric patients: The safety and efficacy of lenvatinib in pediatric patients have not been established. Lenvatinib has been used off-label for children with advanced papillary thyroid carcinoma.

Older patients: In patients with DTC, no differences in safety or efficacy have been marked compared to younger subjects. Similarly, in patients with RCC treated with lenvatinib and pembrolizumab or everolimus, no significant variations in safety or efficacy are apparent between older and younger patients. A recent retrospective cohort study evaluated the efficacy and safety of lenvatinib in patients aged 80 years and older with unresectable HCC. Results showed similar outcomes between older and younger patients, with differing adverse event profiles.[15][16][17][18]

Adverse Effects

The most frequently observed adverse reactions of lenvatinib (≥30% of patients) include hypertension, fatigue, diarrhea, myalgia/arthralgia, reduced appetite, reduced body weight, stomatitis, headache, nausea, vomiting, abdominal pain, dysphonia, proteinuria, palmar-plantar erythrodysesthesia/hand-foot syndrome.[19] Hypertension is one of the most common adverse effects of lenvatinib and is more prominent in subjects aged older than 75.[1][5] During the phase III REFLECT trials for radioactive iodine-refractory DIC, patients from the treatment group reported fistula formation causing bleeding from the tumor. Adverse effects from therapy should be managed supportively with dosing adjustments and discontinuation of treatment if necessary.[20] Other reported adverse effects include the following. The description of severe adverse events includes:

• Rash
• Cardiac dysfunction
• Arterial thromboembolic event
• Hepatotoxicity
• Renal failure or impairment
• Proteinuria
• Gastrointestinal perforation
• Fistula formation 
• QT prolongation
• Hypocalcemia
• Thyroid dysfunction
• Wound healing complications

Drug-Drug Interactions

Lenvatinib is metabolized in the liver by CYP3A4 and aldehyde oxidase.[14] Agents that induce or inhibit the CYP-450 system may alter the plasma concentration of lenvatinib.[21] In addition, lenvatinib prolongs the QTc interval, so concurrent administration of lenvatinib with drugs that prolong the QTc interval should be avoided.[22]

Contraindications

No contraindications are documented in the product labeling of lenvatinib.

Warning and Precautions

Hypertension: Regulating blood pressure before initiating lenvatinib therapy and monitoring throughout treatment is important. In cases of grade 3 hypertension, despite optimal antihypertensive therapy, temporary discontinuation is recommended. For grade 4 hypertension, discontinuation of lenvatinib is warranted.

Cardiac dysfunction: Regular monitoring for signs or symptoms of cardiac dysfunction is essential during therapy. Should grade 3 cardiac dysfunction arise, withholding or discontinuing treatment is advised. For grade 4 dysfunction, immediate discontinuation is necessary.

Arterial thromboembolic events: Following an arterial thromboembolic event, discontinuation of lenvatinib is recommended.

Hepatotoxicity: Liver function should be evaluated before starting treatment and monitored periodically. If grade 3 or 4 hepatotoxicity is detected, withholding or discontinuing lenvatinib is warranted. Complete discontinuation is necessary in cases of hepatic failure.

Renal failure: For grade 3 or 4 renal failure or impairment, temporary withholding or discontinuation of lenvatinib is advised.

Proteinuria: Proteinuria must be monitored regularly before and during lenvatinib therapy. Treatment should be temporarily withheld if proteinuria exceeds 2 g per 24 hours. In cases of nephrotic syndrome, permanent discontinuation is recommended.

Diarrhea: Severe or recurrent diarrhea should be managed promptly. Treatment with lenvatinib should be withheld or discontinued based on the severity of the diarrhea.

Fistula formation and gastrointestinal perforation: If grade 3 or 4 fistula or any gastrointestinal perforation occurs, lenvatinib should be discontinued.

QT interval prolongation: Correcting electrolyte abnormalities is crucial in cases of QT interval prolongation. Treatment should be withheld for a QT interval greater than 500 or a 60 ms or greater increase in baseline QT interval.

Hypocalcemia: Monthly monitoring of serum calcium levels is necessary, with calcium replacement as needed. Treatment with lenvatinib should be withheld or discontinued depending on the severity of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS): Ensure the diagnosis of RPLS with MRI. Lenvatinib should be withheld until RPLS is fully resolved or discontinued if necessary.

Hemorrhagic events: The clinicians should consider the risk of severe and fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels, such as the carotid artery. Upon recovery, lenvatinib can be resumed at a reduced dose or permanently discontinued based on severity.

Thyroid dysfunction: For patients receiving lenvatinib, regular monitoring of thyroid function is required before and during treatment.

Surgery: Before elective surgery, lenvatinib should be withheld for at least 1 week. Following major surgery, treatment should be withheld for at least 2 weeks until adequate wound healing occurs.

Osteonecrosis of the jaw: Consider preventive dentistry before lenvatinib treatment. If possible, invasive dental procedures should be avoided in high-risk patients. Photobiomodulation laser therapy has shown promising results in a case report. Further research is warranted.[21][23][24][23][25][26]

Monitoring

Due to toxicity, several subjects treated with lenvatinib may have their dosage reduced or the drug discontinued. At baseline, creatinine, a pregnancy test for women, an oral exam, blood pressure, and urine protein tests are recommended. Routine monitoring of renal function and liver function is advised. If nephrotic syndrome occurs, treatment should be terminated immediately.[27] ECG monitoring should also be routinely performed since cardiac impairment and QT interval prolongation are adverse effects of using lenvatinib. Thyroid function should be monitored every month, as hypothyroidism may also occur while on therapy. Twenty-four-hour blood pressure monitoring is also advised to detect hypertension from lenvatinib use.[20]

Clinical trials of lenvatinib commonly revealed elevations in serum aminotransferase levels, occurring in 52% of patients. However, values exceeding 5 times the upper limit of normal (ULN) only appeared in 3% to 5% of subjects. Similarly, elevations in serum alkaline phosphatase were also common, occurring in 28% of patients, but were above 3 times ULN in only 2% of patients.[21]

Toxicity

Fetal harm was observed in animal trials during the administration of lenvatinib at a dosage below the recommended range. No reproductive studies have been conducted to analyze the toxicity in humans. Pregnant women should be counseled and advised of possible toxicity to the fetus. Lenvatinib may be present during lactation, and halting breastfeeding is recommended for 1 week following the last dosage.[16]

Enhancing Healthcare Team Outcomes

Lenvatinib is an FDA-approved multiple receptor tyrosine kinase inhibitor indicated for treating radioactive iodine-refractory DTC, unresectable HCC, and advanced RCC. Patients with these malignancies require critical care from an interprofessional team. Early diagnosis and management can decrease life-long complications, improve life quality, and decrease mortality. The interprofessional team includes a primary care clinician, an oncologist, a nurse, and a pharmacist.

Primary care clinicians and specialists should thoroughly educate their patients about the disease course and management and the potential adverse effects of therapy. The primary care clinician, oncologist, and pharmacy oncology specialist team should routinely monitor renal function and liver enzymes, as lenvatinib is metabolized and cleared in the liver and kidneys, respectively, and dosage modifications may be necessary. When treating HCC, the body weight should be routinely monitored, as the therapy dosage is determined based on actual body weight. This is where a specialized oncology pharmacist can provide valuable input.

Lenvatinib has a wide array of adverse effects, and routine follow-ups are vital to prevent complications and long-term harm. Anti-emetics should be considered with the use of lenvatinib due to nausea and vomiting. An EKG is recommended, and the QT interval should be reviewed before selecting which medication to use, as certain anti-emetics can prolong the QT interval. Cardiac impairment and QT-interval prolongation are also adverse effects.

Hypertension is the most reported side effect, and routine blood pressure checks are advised. Early detection can be made by 24-hour blood pressure monitoring. Patients with an underlying history of hypertension should have their blood pressure controlled and maintained in a stable range before initiating therapy. Patients with uncontrolled increases in their blood pressure while receiving optimal treatment for blood pressure should discontinue lenvatinib. In the occurrence of cardiac impairment such as heart failure, cardiomyopathy, or ventricular dysfunction, a cardiologist should be consulted. Thyroid function monitoring should also be routine, as lenvatinib use can result in thyroid gland hypofunction.

During reproductive animal investigations, lenvatinib has been shown to harm the fetus if present in breast milk. Pregnant women should be advised about the likely effects on the fetus and should discontinue breastfeeding for one week following the last dosage of lenvatinib. Interprofessional interaction between healthcare professionals and patients is essential to strengthening rapport and forming a therapeutic alliance. Compliance with therapy is vital in the management of malignancies. This minimizes treatment delays and enhances outcomes and the quality of life. 

A retrospective study evaluated the efficacy of lenvatinib in patients with unresectable radioactive iodine therapy refractory differentiated thyroid cancer across multiple institutions. Fifty-one patients were analyzed, and overall survival and progression-free survival were calculated. Planned drug holidays were implemented to mitigate adverse events. The study found that patients with planned drug holidays experienced significantly improved overall survival, progression-free survival, and time to treatment failure compared to those without planned drug holidays. However, various administration schedules were observed during planned drug holidays. The study underscores the importance of an individualized, patient-centered approach to administration schedules to optimize treatment outcomes in patients with DTC.

A retrospective study investigated the impact of a collaborative program between medical oncologists and pharmacists on managing patients with thyroid cancer undergoing lenvatinib therapy. Pharmacists were pivotal in monitoring patients for adverse reactions, conducting interventions, and consulting with oncologists. The study aimed to prevent unnecessary treatment interruptions or dose reductions through this collaboration. Results indicated that pharmacist interventions significantly reduced treatment interruptions and dose adjustments, improving patient outcomes. This underscores the importance of multidisciplinary teamwork in optimizing medication therapy and enhancing patient care in oncology settings. By implementing an interprofessional team approach that involves clinicians, oncologists, nursing staff, pharmacists, and the patient and their family, the likelihood of successful therapeutic outcomes increases, with a reduced potential for adverse events.[20][28][29]

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Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Mayur Parmar declares no relevant financial relationships with ineligible companies.